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Chromosome aberrations, DNA damage, and risk: Matrix reloaded
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Günter Obe a,1 , Sylvia Ritter b , Marco Durante b,c,∗ a
University of Duisburg-Essen, Essen, Germany GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Planckstraße 1, 64291 Darmstadt, Germany c Technische Universität Darmstadt, Institut für Festkörperphysik, Hochschulstraße 6, 64289 Darmstadt, Germany
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Article history: Received 2 July 2013 Accepted 5 July 2013 Available online xxx
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The first International Symposium on Chromosomal Aberrations (ISCA) was organized at the University of Essen (Germany) in 1989 by G. Obe and A.T. Natarajan. Last, and certainly not least, of a very successful series, the 10th meeting (ISCA10) was held in Amalfi (Italy), on 19–21 October, 2012. Chromosomal aberrations have been studied for decades and still there are lots of open questions. E.J. DuPraw elegantly proved that chromatids of human chromosomes contain single DNA helixes several cm in length [1], but in metaphase the lengths of human chromosomes measure in micrometers due to a high compaction level of chromosomal DNA mainly by proteins. Well before any knowledge of the chemical structure of chromosomes, the classical concepts of chromosomal aberrations were developed using mostly plants and summarized by Douglas Lea in his seminal book “Action of Radiations on Living cells” published in 1946 [2]. It is surprising, in a time where biology evolves so quickly, that most of the concepts described in Lea’s book [2] stood the test of time, and were confirmed by the latest experiments described in ISCA10. As seen in this Special Issue, analyses of the induction of chromosomal aberrations by ionizing radiation are still the focus of experimental cytogenetics. One of the main points discussed at the meeting was the link between DNA repair, whose pathways have been now elegantly elicited by molecular biology, and formation of chromosomal aberrations, especially cancer-prone translocations [3]. FISH methodologies are used to get deeper insights into complex aberration types and are now used routinely in chromosome studies. One early finding using FISH was that the famous
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∗ Corresponding author at: Technische Universität Darmstadt, Institut für Festkörperphysik, Hochschulstraße 6, 64289 Darmstadt, Germany. Tel.: +49 6159 71 2009; fax: +49 6159 71 2106. E-mail address:
[email protected] (M. Durante). 1 Retired. Present address: Gershwinstr. 33, 14513 Teltow, Germany.
linear-quadratic dose-effect relationship of dicentric chromosomes induced by X-rays and analyzed in block-stained preparations results from complex aberrations, whilst simple dicentrics are linearly correlated with radiation dose [4]. Multi-color FISH studies now can give insights into very complex aberration types and have changed our view on the spectrum of aberrations. Reliable analyses of chromosomal aberrations are time consuming and need considerable experience. Surrogate markers are useful for applications where data are needed in short time, such as biodosimetry. Since micronuclei, derived from aberrant chromosomes, are easy to score and give results in a short time, they are often used instead of looking for chromosomal aberrations, but this results in loss of accuracy. Other end points are yH2AX foci in interphase cells indicating the presence of DNA double strand breaks which are actually the ultimate lesions for the formation of chromosomal aberrations; though a 1:1 relationship between these end-points cannot be expected to occur. Most of the studies presented at ISCA10 dealt with radiationinduced aberrations, and the new models of chromosome aberration formation [5] heavily rely on the current molecular knowledge of DNA damage and repair, even though they still exploit the breakage-and-reunion approach described by Lea [2]. Generally adverse outcomes such as cancer are associated with chromosomal aberrations, but the evolution of karyotypes depends on chromosomal rearrangements and this may be the main biological reason for their occurrence. Molecular epidemiology has shown that an increased load of chromosomal aberrations is associated with an increased cancer risk [6]. Chromosome aberrations are therefore essentially the only validated biomarker of cancer risk. Even though the road from DNA damage to cancer is very long and comprises a number of different steps, certainly chromosome rearrangements play quite a big role, especially for some cancers. There are still shortcomings in our understanding of the mechanisms of aberration formation. We are not yet able to reliably connect morphological findings of chromosomal aberrations and
1383-5718/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.mrgentox.2013.07.002
Please cite this article in press as: G. Obe, et al., Chromosome aberrations, DNA damage, and risk: Matrix reloaded, Mutat. Res.: Genet. Toxicol. Environ. Mutagen. (2013), http://dx.doi.org/10.1016/j.mrgentox.2013.07.002
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the molecular knowledge of various types of repair pathways. A great effort in the DNA repair community is dedicated to elucidate the precise steps leading to the formation of translocations. As noted in the debate at ISCA10, to some molecular biologists the study of chromosome aberrations may seem a relic from the past. On the contrary, a close collaboration between cytogenetics and DNA repair experts is essential if we are to “join the break” between DNA lesions and chromosome aberrations [3]. References
[2] D.E. Lea, Actions of Radiations on Living Cells, Cambridge, University Press, 1946. [3] M. Durante, J.S. Bedford, D.J. Chen, S. Conrad, M.N. Cornforth, A.T. Natarajan, D.C. van Gent, G. Obe, From DNA damage to chromosome aberrations: joining the break, Mutat. Res. (2013) (in this issue). [4] P.J. Simpson, J.R.K. Savage, Dose-response curves for simple and complex chromosome aberrations induced by X-rays and detected using fluorescence in situ hybridization, Int. J. Radiat. Biol. 69 (1996) 429–436. [5] W. Friedland, P. Kundrát, Track structure based modeling of chromosomal aberrations after photon and alpha-particle irradiation, Mutat. Res. (2013) (in this issue). [6] G. Obe, D.C. Lloyd, M. Durante, Chromosome aberrations in human populations and cancer, in: G. Obe, B. Jandrig, G.E. Marchant, H. Schütz, P.M. Wiedermann (Eds.), Cancer Risk Evaluation, Wiley-Blackwell, Weinheim, 2011.
[1] E.J. DuPraw, DNA and Chromosomes, Holt Rinehart and Winston, Inc., New York, 1970.
Please cite this article in press as: G. Obe, et al., Chromosome aberrations, DNA damage, and risk: Matrix reloaded, Mutat. Res.: Genet. Toxicol. Environ. Mutagen. (2013), http://dx.doi.org/10.1016/j.mrgentox.2013.07.002
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